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{{chembox |
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{{chembox |
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| verifiedrevid = 450847811 |
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| ImageFile=Nogalamycin.png |
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| ImageSize=200px |
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| IUPACName= |
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| OtherNames= |
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|Section1={{Chembox Identifiers |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = L059DCD6IP |
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| UNII = L059DCD6IP |
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| CASNo_Ref = {{cascite|correct|??}} |
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| verifiedrevid = 444083391 |
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| CASNo=1404-15-5 |
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|ImageFile=Nogalamycin.png |
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| PubChem = 5289019 |
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|ImageSize=200px |
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| ChEBI = 44504 |
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|IUPACName= |
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| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}} |
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|OtherNames= |
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| ChemSpiderID = 4451071 |
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|Section1={{Chembox Identifiers |
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| SMILES = C1((((O1)O2C((C3=CC4=C(C(=C23)O)C(=O)C5=C(C=C6C(=C5C4=O)O7(((6(O7)C)O)N(C)C)O)O)C(=O)OC)(C)O)OC)(C)OC)OC |
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| CASNo=1404-15-5 |
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| InChI = 1/C39H49NO16/c1-14-32(49-7)39(4,52-10)33(50-8)36(53-14)54-19-13-37(2,48)24(34(47)51-9)15-11-16-21(27(43)20(15)19)28(44)22-18(41)12-17-30(23(22)26(16)42)55-35-29(45)25(40(5)6)31(46)38(17,3)56-35/h11-12,14,19,24-25,29,31-33,35-36,41,43,45-46,48H,13H2,1-10H3/t14-,19-,24-,25-,29-,31+,32-,33-,35+,36-,37-,38+,39+/m0/s1 |
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| PubChem=9810949 |
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| InChIKey = KGTDRFCXGRULNK-JYOBTZKQBE |
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| SMILES=C1((((O1)O2C((C3=C2C(=C4C(=C3)C(=O)C5=C6C(=CC(=C5C4=O)O)7((((C(O6)O7)O)N(C)C)O)C)O)C(=O)OC)(C)O)OC)(C)OC)OC |
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| StdInChI_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChI = 1S/C39H49NO16/c1-14-32(49-7)39(4,52-10)33(50-8)36(53-14)54-19-13-37(2,48)24(34(47)51-9)15-11-16-21(27(43)20(15)19)28(44)22-18(41)12-17-30(23(22)26(16)42)55-35-29(45)25(40(5)6)31(46)38(17,3)56-35/h11-12,14,19,24-25,29,31-33,35-36,41,43,45-46,48H,13H2,1-10H3/t14-,19-,24-,25-,29-,31+,32-,33-,35+,36-,37-,38+,39+/m0/s1 |
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| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}} |
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| StdInChIKey = KGTDRFCXGRULNK-JYOBTZKQSA-N |
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}} |
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|Section2={{Chembox Properties |
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|Section2={{Chembox Properties |
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| Formula=C<sub>39</sub>H<sub>49</sub>NO<sub>16</sub> |
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| Formula=C<sub>39</sub>H<sub>49</sub>NO<sub>16</sub> |
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| MolarMass=787.80 g/mol |
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| MolarMass=787.80 g/mol |
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| Appearance= |
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|Section3={{Chembox Hazards |
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|Section3={{Chembox Hazards |
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| MainHazards= |
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| MainHazards= cardiotoxic |
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| FlashPt= |
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| AutoignitionPt = |
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|Section8={{Chembox Related |
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| OtherFunction_label = |
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| OtherCompounds = ] |
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| OtherFunction = }} |
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'''Nogalamycin''' is an ] antibiotic produced by the soil ] '']''. It has antitumor properties but it is also highly cardiotoxic. The less cardiotoxic semisynthetic analog ] was developed in the 1970s. Currently nogalamycin and menogaril are not used clinically.<ref>. ChemicalBook.com. Accessed November 28, 2012.</ref> |
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'''Nogalamycin''' is an ]. |
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==Biosynthesis== |
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Anthracycline biosynthesis involves the construction of an aglycone core (by a ]) to which one or more sugar residues are attached. Nogalamycin consists of three components: |
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<div style="float:right; padding-left: 10%;"> |
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] |
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] |
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* nogalamycinone (black), the aglycone core |
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* nogalose (magenta) |
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* nogalamine (green) |
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Each component is built separately and then ligated together by a two glycosyltransferases.<ref name="Siitonen2012">Siitonen, V. et al. Identification of Late-Stage Glycosylation Steps in the Biosynthetic Pathway of the Anthracycline Nogalamycin. ChemBioChem 13, 120–128 (2011).</ref> All of the machinery associated with the biosynthesis of nogalamycin are located within the same biosynthetic gene cluster of ''S. nogalater''. |
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{{antiinfective-drug-stub}} |
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{{clear}} |
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===Nogalamycinone biosynthesis=== |
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{{redirect|snoaC|the metabolite of acetylcsyteine|SNOAC}} |
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<div style="float:right; padding-left: 10%;"> |
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] |
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</div> |
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The biosynthetic pathway towards the aglycone core of nogalamycin has been determined by a combination of bioinformatic analysis and cloning of individual components of the biosynthetic pathway.<ref name="Torkkell2001">Torkkell, S. et al. The entire nogalamycin biosynthetic gene cluster of ''Streptomyces nogalater'': characterization of a 20-kb DNA region and generation of hybrid structures. Mol Gen Genomics 266, 276–288 (2001).</ref><ref name="Raty2002">Räty, K. et al. Cloning and characterization of Streptomyces galilaeus aclacinomycins polyketide synthase (PKS) cluster. Gene 293, 115–122 (2002).</ref><ref name="Metsa2003">Metsä-Ketelä, M., Palmu, K., Kunnari, T., Ylihonko, K. & Mäntsälä, P. Engineering Anthracycline Biosynthesis toward Angucyclines. Antimicrob. Agents Chemother. 47, 1291–1296 (2003).</ref> The biosynthetic route is similar to that of aklavinone (the aglycone core of most anthracyclines, including ]), the sole difference being that the first acyl group that is loaded into the PKS is an acetate rather than a propionate. The following genes are involved in the biosynthesis of the core nogalamycinone species:<ref name="Torkkell2001"/><ref name="Sultana2006">Sultana, A. Mechanistic insights into the biosynthesis of polyketide antibiotics. (2006).</ref> |
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* ''sno''a1 (ketosynthase-α) |
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* ''sno''a2 (ketosynthase-β chain length factor) |
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* ''sno''a3 (acyl carrier protein) |
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* ''sno''aD (ketoreductase) |
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* ''sno''aE (aromatase) |
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* ''sno''aM (cyclase) |
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* ''sno''aB (oxygenase) |
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* {{anchor|snoaC}} ''sno''aC (methyltransferase) |
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* ''sno''aL (cyclase) |
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* ''sno''aF (ketoreductase) |
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{{clear}} |
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===Nogalamine and nogalose biosynthesis=== |
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<div style="float:right; padding-left: 10%;"> |
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] |
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</div> |
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The sugar moieties that are attached to nogalamycinone are produced from ]. Although the steps following dTDP-4-keto-6-deoxyglucose have not been confirmed ''in vitro'', the high degree of sequence similarity with homologous enzymes from other organisms suggests that the mechanism proceeds as detailed at right.<ref name="Kharel2011">K. Kharel, M., Lian, H. & Rohr, J. Characterization of the TDP-d-ravidosamine biosynthetic pathway: one-pot enzymatic synthesis of TDP-d-ravidosamine from thymidine-5-phosphate and glucose-1-phosphate. Organic & Biomolecular Chemistry 9, 1799–1808 (2011).</ref> The following enzymes are involved in the biosynthesis of nogalamine and nogalose:<ref name="Sultana2006"/> |
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* ''sno''gJ (dTDP-glucose synthase) |
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* ''sno''gK (4,6-dehydratase) |
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* ''sno''gF (3,5-epimerase) |
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* ''sno''gH (2,3-dehydratase) |
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* ''sno''gN (unknown) |
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* ''sno''gI (aminotransferase) |
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* ''sno''gG (ketoreductase) |
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* ''sno''gC (ketoreductase) |
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* ''sno''gA (N-methyltransferase) |
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* ''sno''gX (N-methyltransferase) |
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* ''sno''gG2 (C-methyltransferase) |
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Note that while much of the literature refers to the final, permethylated carbohydrate moiety as "nogalose",<ref name="Duchamp1971">Duchamp, D. J., Wiley, P. F., Hsiung, V. & Chidester, C. G. Structure, absolute configuration, and chemistry of nogalose. J. Org. Chem. 36, 2670–2673 (1971).</ref> more recent data suggest that the nogalose moiety on nogalamycin is methylated after the nogalamycinone core has been glycosylated.<ref name="Siitonen2012"/> |
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{{clear}} |
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===Nogalamycinone glycosylation and tailoring=== |
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The most noteworthy aspect of the structure of nogalamycin is the dual attachment of nogalamine both through ''O''-glycosylation and also through a carbon-carbon bond at the C2 position of the nogalamycinone core,<ref name="Siitonen2012"/> The following enzymes are involved in the final tailoring steps of nogalamycin. ''Sno''N and ''sno''T are genes in the nogalamycin gene cluster that are likely to catalyze the final hydroxylation: |
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* ''sno''gE (glycosyltransferase) |
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* ''sno''aL2 (hydroxylase) |
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* ''sno''gY (O-methyltransferase) |
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* ''sno''gM (putative O-methyltransferase) |
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* ''sno''gL (putative O-methyltransferase) |
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* ''sno''gD (glycosyltransferase) |
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* ''sno''N/T |
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] |
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==References== |
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{{reflist}} |
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] |